Lymphatics and fibroblasts support intestinal stem cells in homeostasis and injury

Goto, Norihiro; Goto, Saori; Imada, Shinya; Hosseini, Seyyed A.; Yılmaz, Ömer H.

doi:10.1016/j.stem.2022.06.013

Cited by 51 publications

(39 citation statements)

References 65 publications

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“…Conversely, pre-treatment with inhibitors of TGFB receptors suppressed the same markers of regeneration in the epithelium ( Figure 5E ). In response to TGFB1 pre-treatment, mesenchymal cells exhibited higher levels of transcripts expected to promote regeneration/wound healing such as Ptgs2, Wnt5a , and Lif (Miyoshi et al, 2012; Roulis et al, 2020; Wang et al, 2020); lower levels of transcripts that promote homeostatic epithelial growth, such as Grem1 and Rspo3 (Goto et al, 2022; McCarthy et al, 2020) were observed in response to TGFB1 treatment ( Figure 5F ), suggesting that TGFB1 reshapes the signaling environment to favor regenerative growth. Similar changes in transcriptional profiles were observed in vivo within the Pdgfra -expressing populations in response to IR ( Figure S5A ), and mesenchyme isolated from irradiated intestines expressed higher levels of transcripts for pro-regenerative growth ligands and reduced levels of ligands associated with homeostatic growth ( Figure S5B ).…”

Section: Resultsmentioning

confidence: 99%

TGFB1 Induces Fetal Reprogramming and Enhances Intestinal Regeneration

Chen

Dupre

Qiu

et al. 2023

Preprint

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The adult gut epithelium has a remarkable ability to recover from damage. To achieve cellular therapies aimed at restoring and/or replacing defective gastrointestinal tissue, it is important to understand the natural mechanisms of tissue regeneration. We employed a combination of high throughput sequencing approaches, mouse genetic models, and murine and human organoid models, and identified a role for TGFB signaling during intestinal regeneration following injury. At 2 days following irradiation (IR)-induced damage of intestinal crypts, a surge in TGFB1 expression is mediated by monocyte/macrophage cells at the location of damage. Depletion of macrophages or genetic disruption of TGFB-signaling significantly impaired the regenerative response following irradiation. Murine intestinal regeneration is also characterized by a process where a fetal transcriptional signature is induced during repair. In organoid culture, TGFB1-treatment was necessary and sufficient to induce a transcriptomic shift to the fetal-like/regenerative state. The regenerative response was enhanced by the function of mesenchymal cells, which are also primed for regeneration by TGFB1. Mechanistically, integration of ATAC-seq, scRNA-seq, and ChIP-seq suggest that a regenerative YAP-SOX9 transcriptional circuit is activated in epithelium exposed to TGFB1. Finally, pre-treatment with TGFB1 enhanced the ability of primary epithelial cultures to engraft into damaged murine colon, suggesting promise for the application of the TGFB-induced regenerative circuit in cellular therapy.

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Section: Resultsmentioning

confidence: 99%

TGFB1 Induces Fetal Reprogramming and Enhances Intestinal Regeneration

Chen

Dupre

Qiu

et al. 2023

Preprint

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“…Moreover, the trajectory analysis of spatial transcriptomic data enabled us to observe the selective activation of some genes at the early stages of pseudotime, confirming the progenitor nature of this subpopulation. In addition, the microenviroment of this cluster is rich in adherens junctions and vascular cells, which are essential in cell-cell communication, cell renewal and differentiation 48,49 . All these findings suggest that these ID1 + cells might represent a new progenitor population in the adult adrenal cortex.…”

Section: Discussionmentioning

confidence: 99%

Cell Atlas at Single-Nuclei Resolution of the Adult Human Adrenal Gland and Adrenocortical Adenomas

Altieri

Secener

Sai

et al. 2022

Preprint

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The human adrenal gland is a complex endocrine tissue. Developmental studies on this tissue have been limited to animal models or human foetus. Here, we present a cell atlas analysis of the adult human normal adrenal gland, combining single-nuclei RNA sequencing and spatial transcriptome data to reconstruct adrenal gland development and tumourigenesis. We identified two populations of potential progenitor cells resident within the adrenal cortex: adrenocortical progenitors NR2F2+-ID1+ cells, located within and underneath the capsule, and medullary progenitors SYT1+-CHGA- cells, located in islets in the subcapsular region. Using pseudotime analyses, we provided evidence of the centripetal nature of adrenocortical cell development and of the essential role played by the Wnt/β-catenin pathway in the adrenocortical self-renewal. By comparing transcriptional profiles of cells of normal adrenal glands and adrenocortical adenomas we revealed a high heterogeneity with six adenoma-specific clusters. Overall, our results give insights into adrenal plasticity and mechanisms underlying adrenocortical tumourigenesis.

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“…LECs are resistant to IR-related apoptosis and expand after IR exposure, where they serve as an essential source of pro-regenerative niche factors such as RSPO3, Wnt2a, and Ccl21a (Goto et al, 2022; Niec et al, 2022; Ogasawara et al, 2018; Palikuqi et al, 2022). Given this established role of lymphatics in intestinal regeneration, we sought to investigate if there could be crosstalk between LECs and Hdc + IMCs after injury.…”

Section: Resultsmentioning

confidence: 99%

“…Pre-collector LECs surround the crypt base and associate with ISCs to regulate their activity (Niec et al, 2022). This LEC population expands in the intestine after whole-body irradiation (WB-IR), and conditional knockout of the Rspo3 gene in LECs hinders intestinal regeneration after WB-IR or 5FU chemotoxic injury, highlighting the importance of LEC-derived RSPO3 in this setting (Goto et al, 2022; Palikuqi et al, 2022). Lymphatics also expand in the bone after WB-IR and participate in regeneration (Biswas et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

Immature myeloid cells are indispensable for intestinal regeneration post irradiation injury

Jiang

Waterbury

et al. 2023

Preprint

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SUMMARYThe intestinal epithelium functions both in nutrient absorption and as a barrier, separating the luminal contents from a network of vascular, fibroblastic, and immune cells underneath. Following injury to the intestine, multiple different cell populations cooperate to drive regeneration of the mucosa. Immature myeloid cells (IMCs), marked by histidine decarboxylase (Hdc), participate in regeneration of multiple organs such as the colon and central nervous system. Here, we found that IMCs infiltrate the injured intestine and promote epithelial regeneration and modulate LEC activity. IMCs produce prostaglandin E2 (PGE2), which promotes LEC lymphangiogenesis and upregulation of pro-regenerative factors including RSPO3. Moreover, we found that IMC recruitment into the intestine is driven by invading microbial signals. Accordingly, antibiotic eradication of the intestinal microbiome prior to WB-IR inhibits IMC recruitment, and consequently, intestinal recovery. We propose that IMCs play a critical role in intestinal repair and implicate gut microbes as mediators of intestinal regeneration.

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Lymphatics and fibroblasts support intestinal stem cells in homeostasis and injury

Cited by 51 publications

References 65 publications

TGFB1 Induces Fetal Reprogramming and Enhances Intestinal Regeneration

TGFB1 Induces Fetal Reprogramming and Enhances Intestinal Regeneration

Cell Atlas at Single-Nuclei Resolution of the Adult Human Adrenal Gland and Adrenocortical Adenomas

Immature myeloid cells are indispensable for intestinal regeneration post irradiation injury

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